Study On Nasal Spray Of Naloxone Hydrochloride

Naloxone Hydrochloride is a pure opioid receptor antagonist .It is widely used for the treatment of intoxication of anaesthetic and alcohol, shock, brain infarction and so forth with good curative effect and few side effect. Because of a serious liver first-pass effect, the dosage forms of Naloxone Hydrochloride is mainly used on domestic and aboard clinical practice in the forms of injection and sublingual tablet. Intravenous administration of Naloxone Hydrochloride needs special environment and will cause some injury to patients. Sublingual administration takes on action slowly (15-30min) and it is inconvenient for the patients of coma to use. In order to provide an alternative administration of Naloxone Hydrochloride for systemic drug delivery and improve patient compliance, considering the physiochemical properties of Naloxone Hydrochloride and the characteristics of intranasal administration, we planed to study on the nasal spray of Naloxone Hydrochloride.The optimization of the formulation was the key work in our study. We established an in vitro method to evaluate the transmucosa absorption of Naloxone Hydrochloride with various absorption enhancers. An effective absorption enhancer was found with the index of accumulative permeation. Then the effects of different concentrations of this enhancer on the transmucosa absorption extent and the ciliotoxicity were investigated respectively. Based on the study above, the optimal concentration of this enhancer was determined. The result showed that the accumulative permeation of Naloxone Hydrochloride with this enhancer was 2-3 times higher than that without enhancer. After selection of solvent, pH, antiseptic and administration instrument, the formulation of the dosage form was determined.In order to control the quality of the preparation, a reliable HPLC method of determination of Naloxone Hydrochloride and its relative substances was established.Under the condition of test, the pharmaceutical aids and the decomposition products could be well separated from Naloxone Hydrochloride. The stability study on nasal spray indicated that it was stable, nearly without any changes during the stability study.The ciliotoxicity of the preparation was investigated by using index of ciliary vibration duration by in vitro method. The result showed that the preparation had little ciliotoxicity and the ciliotoxicity was reversible. The irritation test in eyes of rabbits indicated the preparation has little irritation to the mucosa.The pharmacodynamic study of the preparation on rabbits showed that Naloxone Hydrochloride could be absorbed rapidly and played a systemic role after nasal administration. The effect of nasal administration that reversed opioids was comparable to that of i.m. administration.The pharmacokinetics and bioavailability study of the nasal spray of Naloxone Hydrochloride was carried out on 6 Beagle dogs in a randomized crossover manner. The drug plasma concentrations were determined by HPLC. The concentration-time curves conformed to 2-compartment model with first-order absorption. Tmax and Cmax were 10min and 279.49ng ml-1 respectively. The absolute bioavailability of the preparation was 87.88%.This enhancer found in the optimization of formulation could improve the accumulative permeation of Naloxone Hydrochloride for 2-3 times .No report about it was found. The innovation of the formulation was verified by the pharmacodynamic and pharmacokinetics studies of Naloxone Hydrochloride nasal spray. The preclinical study of it as 2nd category new drug of China have been finished basically. Patents of it will be applied.